Maintenance of PARP Inhibitor Rechallenge Plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP Inhibitor (KGOG 3056/NIRVANA-R)

Maintenance of PARP Inhibitor Rechallenge Plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP Inhibitor (KGOG 3056/NIRVANA-R) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Maintenance of PARP Inhibitor Rechallenge Plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP Inhibitor (KGOG 3056/NIRVANA-R) Jung Yun Lee, Hyun-Woong Cho, Jeong-Yeol Park, Myong Cheol Lim, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6280645/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical benefit in prolonging progression-free survival (PFS) in ovarian cancer. However, the efficacy of subsequent chemotherapy after PARPi progression is limited. While modest benefits have been seen with PARPi rechallenge, the efficacy of rechallenging with PARPi in combination with bevacizumab remains unknown. NIRVANA-R, a phase 2 study, evaluated niraparib rechallenge with bevacizumab in 44 patients with platinum-sensitive recurrent ovarian cancer previously treated with PARPi. The estimated 6-month PFS rate, the primary endpoint, was 68% [95% confidence interval (CI): 55–85%]. Notably, higher 6-month PFS rates were observed in patients with a longer treatment-free interval after the penultimate chemotherapy and in those who achieved a complete response to the most recent chemotherapy. Median PFS was 11.5 months [95% CI: 7.9–not reached]. This is the first report of niraparib rechallenge with bevacizumab as maintenance therapy in this patient population. The combination showed promising efficacy, especially in patients who responded well to prior platinum-based chemotherapy. Health sciences/Oncology/Cancer/Gynaecological cancer/Ovarian cancer Health sciences/Oncology/Cancer/Gynaecological cancer Figures Figure 1 Figure 2 Figure 3 Introduction Maintenance therapy with PARP inhibitors (PARPi) is the standard of care in patients with newly diagnosed advanced and platinum-sensitive, recurrent ovarian cancer, particularly in PARPi-naïve patients. 1, 2, 3, 4, 5, 6 This approach has significantly improved progression-free survival (PFS), and in the case of olaparib, has also demonstrated an overall survival (OS) benefit, leading to its integration into treatment paradigms worldwide 7, 8 . However, despite the clear benefit of PARPi in ovarian cancer, most patients eventually develop treatment resistance. 2, 3, 4, 5, 6, 9, 10 After progression on PARPi maintenance, the response to subsequent chemotherapy is reduced in ovarian cancer patients compared to those who were not previously administered PARPi. 10, 11, 12 Therefore, choosing subsequent therapy for patients who relapse after maintenance with a PARPi is challenging. 10, 13, 14 Recent studies have explored the concept of PARPi rechallenge in this context. 13, 15, 16 Although rechallenging with a PARPi after a response to platinum-based chemotherapy has demonstrated a modest benefit for PFS, 15, 16 the extent of this benefit and which patients might benefit most from this strategy is still under investigation. The OReO/ENGOT Ov-38 trial specifically addressed this clinical question by evaluating the efficacy and safety of PARPi rechallenge in patients with ovarian cancer who had previously received PARPi maintenance. 13 The results of this study have provided critical insights into the potential role of PARPi rechallenge in this patient population highlighting the need for further research to optimize maintenance therapy strategies in recurrent ovarian cancer. PARPi combined with anti-angiogenic agents have shown promising efficacy, particularly in the treatment of ovarian cancer. 17, 18, 19, 20, 21 The combination therapy works by using bevacizumab to induce hypoxia in the tumor microenvironment, which can lead to homologous recombination deficiency (HRD) in cancer cells. 22 This HRD makes cancer cells more vulnerable to PARPi, and since the cells are unable to repair DNA damage, the effectiveness of the treatment is enhanced. This study aimed to build on these findings by investigating the combination of PARPi rechallenge with bevacizumab as maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer who had previously been treated with a PARPi. Results A total of 44 women were enrolled between July 2021 and November 2023. In our cohort, 39 patients (89%) had high-grade serous ovarian cancer, and 36% harbored somatic and/or germline BRCA1/2 mutations (Table 1 ). Additionally, 29 patients (66%) had received more than three prior lines of chemotherapy, 17 patients (39%) were included after receiving a maintenance PARPi as part of first-line therapy, and 34% had previously received anti-angiogenics (bevacizumab). Table 1 Patient Characteristics at Baseline Niraparib + Bevacizumab (n = 44) Age, years, median (IQR) 60 (53–67) ECOG performance status score, n (%) 0 33 (75%) 1 11 (25%) Histology type, n (%) High-grade serous 39 (89%) Others + 5 (11%) BRCA status, n (%) BRCA mutation 16 (36%) BRCA wild-type 22 (50%) Unknown 6 (14%) Number of prior lines of chemotherapy, n (%) 2nd line 15 (34%) 3rd line and beyond 29 (66%) Platinum-free interval (TFIp) of penultimate chemotherapy, n (%) ≧12 to < 24 months 24 (55%) ≧24 months 20 (45%) Response to the most recent chemotherapy PR (Partial response) 27 (61%) CR (Complete response) 17 (39%) Previous anti-angiogenic use Yes 15 (34%) No 29 (66%) Progression on/after previous PARPi, n (%) Progression during PARPi 30 (68%) Progression after PARPi 14 (32%) Duration of previous PARPi, n (%) <12 months 6 (14%) ≧12 months 38 (86%) Line of previous PARPi, n (%) 1 17 (39%) 2 14 (31%) 3 and beyond 13 (30%) Number of previous PARPi, n (%) 1 43 (98%) 2 1 (2%) Type of previous PARPi Olaparib 23 (52%) Niraparib 19 (43%) Rucaparib 2 (5%) + 3 Endometrioid, 2 low grade serous. PARPi = PARP inhibitor. ECOG = Eastern Cooperative Oncology Group The median duration of follow-up was 11·8 months at the data collection cut-off (June 1, 2024). About 31 patients discontinued trial treatment, while 13 continued (eFigure 1 in the Supplement). The reasons for study discontinuation were disease progression (n = 21), withdrawn consent (n = 5), adverse events (n = 3), and physicians' decision to discontinue study treatment (n = 2). The estimated 6-month progression-free rate was 68% [95% confidence interval (CI) 55–85%], with a median PFS of 11·5 months [95% CI 7.9-not reached (NR)] (Fig. 1 ). The estimated 12-month progression-free rate was 46% (95% CI 31–68%) (Fig. 1 ). The treatment overview for each patient, including the treatment-free interval (TFI P, platinum) after penultimate platinum-based chemotherapy and duration of doublet maintenance therapy, is shown in Fig. 2 . The 6-month time point from the start of doublet maintenance is marked with a vertical dashed line (Fig. 2 ). About 20 patients had a TFI P ≥24 months after penultimate chemotherapy, and 43 patients had received PARPi as maintenance. In the cohort, 12 of the 44 patients showed disease progression within 6 months. This suggests that patients with a longer TFI P benefit more from doublet maintenance therapy with niraparib and bevacizumab, indicating that TFI P is a critical prognostic factor for better outcomes in terms of PFS. Exploratory subgroup analysis suggested an enhanced 6-month progression-free rate with maintenance of niraparib plus bevacizumab in patients with a long TFI P after penultimate platinum-based chemotherapy (TFI P ≥24 months vs. TFI P <24 months; 82% vs. 56%), in patients who had a complete response (CR) to the most recent chemotherapy [CR vs. partial response (PR); 86% vs. 57%], and in patients with normal-range CA-125 levels after the most recent chemotherapy (CA-125 0–35 vs. >35 U/mL; 72% vs. 25%) (Fig. 3 , eFigure 2 in the Supplement). No clear association was observed between the number of prior lines of chemotherapy (≤ 2 vs. >3), BRCA status, duration of prior PARPi exposure, type of previous PARPi (olaparib, niraparib, and rucaparib), progression during/after PARPi, or prior use of bevacizumab and the efficacy of niraparib plus bevacizumab maintenance (Fig. 3 ). No new safety signals were observed for niraparib and bevacizumab treatment. The treatment-related adverse events (TRAEs) reported during the study are shown in Table 2 . Grade ≥ 3 TRAEs were reported in 12 (27·3%) patients. TRAEs were usually managed by dose modification, with only a few patients requiring discontinuation of treatment due to TRAEs (4 patients, 9.1%). None of the TRAEs resulted in death. eTable 3 in the Supplement presents the most common all-grade adverse events, which were thrombocytopenia (29·6%), hypertension (20·5%), anemia (18·2%), and neutropenia (18·2%). Overall, 27·3% of patients experienced grade 3 adverse events, with the most common being anemia (13·6%) and neutropenia (13·6%). The most common grade ≥ 3 niraparib-related and bevacizumab-related TRAEs were thrombocytopenia (27·3%) and hypertension (13·6%). No cases of Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML) were observed. Table 2 Summary of Adverse Events Parameter, n (%) Overall N = 44 Any TRAE 40 (90·9%) Niraparib related 36 (81·8%) Bevacizumab related 29 (65·9%) Any grade ≧ 3 TRAE 12 (27·3%) Niraparib related 12 (27·3%) Bevacizumab related 6 (13·6%) Any TRAE leading to discontinuation of any study treatment 4 (9·1%) Discontinuation of niraparib 3 (6·8%) Discontinuation of bevacizumab 2 (4·5%) Any TRAE leading to study treatment interruption 26 (59·1%) Niraparib interruption 20 (45·5%) Niraparib dose reduction 10 (22·7%) Bevacizumab interruption 14 (31·8%) Any TRAE leading to death 0 TRAE = Treatment-Related Adverse Events Discussion KGOG3056/NIRVANA-R is the first trial to report data on PARPi rechallenge with bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer patients who were previously treated with a PARPi. This study evaluated the doublet maintenance of niraparib rechallenge plus bevacizumab and demonstrated promising results. The study showed a 6-month progression-free rate of 68% and a median PFS of 11·5 months in patients with platinum-sensitive recurrent ovarian cancer who experienced disease progression after PARPi therapy. The findings from the NIRVANA-R study, which reported a 6-month progression-free rate of 68% and a median PFS of 11·5 months for PARPi rechallenge with bevacizumab, can be compared to results from the OReO and MOLTO studies, both of which explored PARPi rechallenge strategies in recurrent ovarian cancer. All three studies included patients with platinum-sensitive recurrence who had prior PARPi exposure, making them comparable in terms of study population. The OReO trial demonstrated that platinum-sensitive patients with relapsed ovarian cancer, who were previously treated with a PARPi, had a median PFS of 4·3 months in the overall population and 4·5 months in the BRCA-mutated cohort when rechallenged with olaparib, compared to 2·8 and 2·2 months, respectively, in patients administered placebo. 13 This suggests that PARPi rechallenge alone provides modest benefits, but not as robust as the combination approach seen in NIRVANA-R. On the other hand, the MOLTO study, which evaluated olaparib rechallenge in a similar population with BRCA mutations, reported a median duration of olaparib rechallenge of 4·4 months, indicating that the addition of bevacizumab in NIRVANA-R may enhance the efficacy of PARPi rechallenge. 16 Overall, these results indicate that PARPi rechallenge can offer disease control in selected patients, but combining it with bevacizumab may further improve patient outcomes. NIRVANA-R provides meaningful insights into which patients may benefit from about PARPi rechallenge. The 6-month progression-free rate was notably higher in patients with a longer TFI P after penultimate platinum-based chemotherapy, those who achieved a CR to the most recent chemotherapy, and those with normal-range CA-125 levels at baseline. These findings suggest that patients with a longer TFI P after penultimate chemotherapy, a CR to the most recent chemotherapy, or normal CA-125 levels at baseline benefited more from the combination of niraparib and bevacizumab. These results align with findings from the OReO study, in which patients who had a CR at baseline and a longer platinum-free interval between penultimate and the most recent platinum-based chemotherapy experienced greater benefit from olaparib rechallenge. 13 In both the OReO and NIRVANA-R trials, the median PFS significantly improved in these subgroups, highlighting the importance of baseline characteristics in predicting the efficacy of PARPi rechallenge. Despite the significant findings in certain subgroups, this study found no clear association between the efficacy of niraparib plus bevacizumab maintenance therapy and factors such as the number of prior lines of chemotherapy (≤ 2 vs. >3), BRCA status, duration of prior PARPi exposure, type of previous PARPi (olaparib, niraparib, or rucaparib), progression during or after PARPi, and historical use of bevacizumab. The lack of significant differences in PFS based on the number of prior lines of chemotherapy is consistent with the findings from the OReO study, which also observed minimal variation in PFS across different prior treatment lines. Similarly, in both the present study and the OReO study, no significant differences in PFS were observed based on BRCA status. 13 However, the absence of substantial differences in PFS based on whether progression occurred during or after PARPi treatment differs from the findings reported in the OReO study and the PAOLA-1 post-hoc analysis, which showed a more pronounced difference in outcomes based on the timing of progression relative to PARPi use. 12 Nonetheless, the NIRVANA-R study also indicated some variation in PFS between the two groups and reported a median PFS of 11·3 months in patients with disease progression during PARPi treatment and PFS of 14·9 months in patients with disease progression after PARPi treatment. While this difference was not significant, the numerically longer PFS in the progression-after-PARPi group suggests that patients who experience progression after completing PARPi may still respond to subsequent platinum therapy. In contrast, those who progress on PARPi may exhibit poorer responses to platinum but could still be considered for PARPi retreatment if they demonstrate sensitivity to subsequent platinum-based regimens. While the NIRVANA-R study provides valuable insights into the efficacy of PARPi rechallenge combined with bevacizumab in recurrent ovarian cancer, it leaves several critical questions unanswered that need to be addressed in future research. One key limitation of this study is that the efficacy of PARPi rechallenge in patients who relapse after a certain period following the completion of PARPi therapy, particularly after a treatment-free interval, still needs to be investigated. Another important aspect requiring further investigation is understanding the reason for discontinuing the initial PARPi therapy, whether due to disease progression or other factors such as adverse events, and how this affects prognosis and response to subsequent PARPi rechallenge. Addressing these questions will be crucial in refining patient selection for PARPi rechallenge and optimizing treatment strategies for recurrent ovarian cancer. The NIRVANA-R study's safety profile demonstrated manageable adverse events that were similar to those reported in other studies involving PARPi rechallenge or PARPi-bevacizumab combinations (such as OREO, PAOLA-1, and OVARIO). In the NIRVANA-R study, the most common all-grade adverse events included thrombocytopenia (29·6%), hypertension, anemia, and neutropenia, and 27·3% of patients reported grade ≥ 3 events. These findings are comparable to that of the OVARIO study where the most common any-grade adverse events related to niraparib and/or bevacizumab were thrombocytopenia, fatigue, and anemia. 23 However, the NIRVANA-R study reported a slightly lower incidence of severe (grade ≥ 3) events compared to the PAOLA-1 study (57%) and OVARIO study (39%). 17, 23 The OREO study which focused on olaparib rechallenge also observed similar incidence of hematological toxicities such as anemia and neutropenia, but reported a lower incidence of hypertension and thrombocytopenia compared to NIRVANA-R. 13 Despite these differences, the rates of dose modifications and treatment discontinuations due to adverse events were comparable between NIRVANA-R and OREO. A comparison of these findings suggested that a combination of niraparib and bevacizumab in NIRVANA-R is consistent with known safety profiles from similar studies, indicating that the addition of bevacizumab did not substantially increase the toxicity of PARPi rechallenge. Importantly, no new safety signals were identified in NIRVANA-R and no cases of treatment-related deaths were reported, highlighting the manageable safety profile of the niraparib and bevacizumab combination in this setting. This study has several strengths including a robust exploration of the efficacy of PARPi rechallenge combined with bevacizumab in recurrent ovarian cancer. The study design allowed for meaningful subgroup analyses, providing insights into the profile of patients which may benefit the most from this treatment approach, especially patients with a longer TFI P after penultimate platinum-based chemotherapy and favorable responses to most recent platinum-based chemotherapy. However, the study has some limitations. The sample size is relatively small. This may limit the generalizability of the findings. Additionally, the subgroup analysis was exploratory in nature and was not sufficiently statistically powered for definitive conclusions. This emphasizes the need for cautious interpretation of these results. The present study did not meet its primary endpoint, but this may be due to an overly optimistic statistical assumption rather than a lack of treatment efficacy. At the time of the study, there was limited clinical evidence indicating that patients who relapse after PARPi maintenance therapy often exhibit reduced responses to subsequent chemotherapy. The anticipated 6-month progression-free rate of 50% without doublet maintenance may have been an overestimate for this population. In the OREO study, for example, the placebo group had a PFS of only 2·8 months, with a 6-month progression-free rate of approximately 10%. 10 Similar finding have been reported in other studies involving PARPi. 10 In conclusion, although the NIRVANA-R study did not meet its predefined primary endpoint, the study provides important insights into the potential role of PARPi rechallenge with bevacizumab as a maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer who were previously been treated with a PARPi. The study demonstrated a 6-month progression-free rate of 68% and a median PFS of 11.5 months in overall population, with more pronounced benefits observed in subgroups such as, those with a longer TFI P after penultimate platinum-based chemotherapy, CR or normal CA-125 level in response to the most recent chemotherapy. However, the study raises important questions about the impact of historical PARPi exposure and the timing of progression on the efficacy of rechallenge, underscoring the need for further research to refine patient selection and optimize treatment strategies. Overall, while the combination of niraparib and bevacizumab is promising, more definitive studies are needed to fully understand its role in managing recurrent ovarian cancer after PARPi therapy. Methods Study Design and Participants The KGOG 3056/NIRVANA-R trial is a multi-center, investigator-initiated, single-arm phase II trial designed to evaluate the combination of niraparib and bevacizumab as maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer who were previously treated with a PARPi. Eligible patients were offered niraparib and bevacizumab as maintenance treatment, continued until unacceptable toxicity developed or the patient no longer derived clinical benefit due to disease progression. The major inclusion criteria for the trial were as follows: prior treatment with a PARPi; ≥2 previous courses of platinum-based chemotherapy; complete or partial response to the most recent platinum-based chemotherapy; TFI P from penultimate platinum-based chemotherapy of ≥ 12 months; serous, clear cell, or low-grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; age ≥ 20 years; and ECOG performance status of 0–1. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Approval was obtained from national and local research ethics committees, and all patients provided written informed consent. Procedures Patients were enrolled within 8 weeks of receiving their last dose of platinum-based chemotherapy. Oral niraparib (individual starting dose of 200 or 300 mg) was administered once daily, and bevacizumab (15 mg/kg) was administered every 3 weeks as an intravenous infusion. 24 Treatment continued until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first. Tumors were assessed every 12 weeks according to RECIST v1·1 until radiologic progression. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4·03). Adverse events were graded according to version 5·0 of the same criteria. Criteria for treatment interruptions and dose reductions are provided in the Supplementary Information. Provision of archival tissue (initial diagnostic tissue before PARPi treatment) was mandatory, while baseline biopsy (after PARPi) and blood samples were optional. Outcomes The primary objective was to determine the efficacy of niraparib plus bevacizumab maintenance therapy in patients previously treated with a PARPi, as assessed by the 6-month progression-free rate. Progression was defined according to RECIST (version 1·1), including progression without objective evidence, such as global deterioration in health status attributable to disease and requiring a change in therapy. The secondary objectives were to evaluate the 12-month progression-free rate, PFS, OS, time until the first subsequent treatment (from randomization until first subsequent surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, other treatment, or death), safety, and predictive biomarkers correlated with response to niraparib plus bevacizumab. PFS was defined as the time from the start of treatment until disease progression or death from any cause. OS was defined as the time from the first treatment until death from any cause. Statistical Analysis Clinical characteristics were summarized as frequency (percentage) for categorical variables and as mean ± standard deviation (SD) for continuous variables. Sample size computation was based on a Simon optimal two-stage design. Assuming a 5% significance level and 80% statistical power, we hypothesized a 50% 6-month progression-free rate under the null hypothesis and at least 70% under the alternative hypothesis for patients with platinum-sensitive recurrent ovarian cancer. In the first stage, 22 patients were enrolled. If 9 or fewer progressions were observed at 6 months, an additional 22 patients were enrolled later. Hence, a total of 44 patients were enrolled. The safety evaluable set included all patients who began treatment. The 6-month and 12-month progression-free rates were estimated using the Kaplan-Meier method and were compared between groups using the log-rank test. All reported P -values were two-sided, a P -value < 0·05 was considered significant. All data analyses were performed using R software (version 4·4·1; R Foundation for Statistical Computing, Vienna, Austria). Data collection cut-off date was set as June 1, 2024. Declarations Author Contributions JYL contributed to the design of the study. JYP, MCL, BGK, MCC, JWK, DHJ, JYL and HWC Korea Gynecologic Oncologic Group (KGOG) members recruited patients and collected the data. HWC, SBH and JYL contributed to data analysis and interpretation. HWC, EP and JYL drafted the manuscript. HWC and JYL verified all study data. The final version was approved to be submitted by all authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of interest Jung-Yun Lee Consulting or Advisory Role: AstraZeneca, MSD, Roche, Takeda Research Funding: Clovis Oncology, Immunogen, Janssen Oncology, Merck, MSD, Synthon, Eisai, Mersan, Ascendis Pharma, AstraZeneca, Novartis, OncoQuest Pharmaceutical, Roche, Seagen, Takeda No other potential conflicts of interest were reported. Funding National Cancer Center of the Republic of Korea Data availability De-identified participant data will be accessible to qualified researchers upon request, commencing 24 months after the study’s completion, including follow-up. Interested researchers should submit a methodologically sound research proposal to the corresponding author and sign a data access agreement to obtain access. Acknowledgments This research was funded by a grant under the National Cancer Center of the Republic of Korea (No. : RS-2024-00360954) References Ledermann J , et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. 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EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. Clin Cancer Res 26 , 4206-4215 (2020). Morgan RD , et al. Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial. Clin Cancer Res 29 , 2602-2611 (2023). Ray-Coquard I , et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med 381 , 2416-2428 (2019). Liu JF , et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15 , 1207-1214 (2014). Mirza MR , et al. A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV24. Cancer Chemother Pharmacol 84 , 791-798 (2019). Kim YN , et al. Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045. Int J Cancer 153 , 2032-2044 (2023). Kim YN , et al. Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4. Nat Commun 14 , 5476 (2023). Alvarez Secord A, O'Malley DM, Sood AK, Westin SN, Liu JF. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecol Oncol 162 , 482-495 (2021). Hardesty MM , et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Gynecol Oncol 166 , 219-229 (2022). Li N , et al. Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol 9 , 1230-1237 (2023). Additional Declarations There is NO Competing Interest. Supplementary Files SupplementarymaterialsHWCHO20250318.docx Supplementary materials NIRVANARprotocolVer1.44clean20230207.docx.pdf NIRVANA-R protocol Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6280645","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":441815323,"identity":"6dff065b-e400-4938-ad6a-955c0d80e1d2","order_by":0,"name":"Jung Yun Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBAC9hk5hp952w4n2M8/fICBsYEILYwz8oyledseJxhIsCUQqyXfjHFm22egFh4D4rUwfIRo+SbNu6OOgb/9ACEtudsYEttuJ9jL926T5j1zmEHiTAJhLRYgLQYSvEAtbUAbbhB0WM43icS28yCHPQNqqWOQJ6RFcEZOGVDLcZAWNqAWZgYDQlqkec4USyScAWlhM7ac23aYx5CQX/jYeww/JFQcrgdG5cMbb9vq5OSOHyBgDRJgkQASPMSrBwLmDyQpHwWjYBSMghEDABtKSOjnMol8AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4094-2097","institution":"Yonsei University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jung","middleName":"Yun","lastName":"Lee","suffix":""},{"id":441815324,"identity":"05d1ea3a-5f36-466b-b6c3-bf5bdf965960","order_by":1,"name":"Hyun-Woong Cho","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyun-Woong","middleName":"","lastName":"Cho","suffix":""},{"id":441815325,"identity":"dd7bb071-230e-496e-8576-dc5588ebd10e","order_by":2,"name":"Jeong-Yeol Park","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeong-Yeol","middleName":"","lastName":"Park","suffix":""},{"id":441815326,"identity":"13f25b88-667f-4fa1-ba25-bc2ed6763e81","order_by":3,"name":"Myong Cheol Lim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Myong","middleName":"Cheol","lastName":"Lim","suffix":""},{"id":441815327,"identity":"9ecf1499-1775-4132-803d-e51eb34734c0","order_by":4,"name":"Byoung-Gie Kim","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Byoung-Gie","middleName":"","lastName":"Kim","suffix":""},{"id":441815328,"identity":"a5457fc0-8ba2-45b1-a0e0-730a87370df6","order_by":5,"name":"Seungbong Han","email":"","orcid":"","institution":"Korea University","correspondingAuthor":false,"prefix":"","firstName":"Seungbong","middleName":"","lastName":"Han","suffix":""},{"id":441815329,"identity":"b66818d8-c9e3-441a-a0e8-62b8288e3ed2","order_by":6,"name":"Min Chul Choi","email":"","orcid":"","institution":"CHA Bundang Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"Chul","lastName":"Choi","suffix":""},{"id":441815330,"identity":"cda27014-ff54-458e-890c-c91bf14390f2","order_by":7,"name":"Jae-Weon Kim","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Seoul National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jae-Weon","middleName":"","lastName":"Kim","suffix":""},{"id":441815331,"identity":"d0306578-a01f-4f04-a1e1-73d3c15c2871","order_by":8,"name":"Dae Hoon Jeong","email":"","orcid":"","institution":"Busan Paik Hospital, Inje University","correspondingAuthor":false,"prefix":"","firstName":"Dae","middleName":"Hoon","lastName":"Jeong","suffix":""},{"id":441815332,"identity":"6a421657-9536-4de8-8b40-722f28b1ac85","order_by":9,"name":"Eric Pujade-Lauraine","email":"","orcid":"https://orcid.org/0000-0002-0759-7263","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Pujade-Lauraine","suffix":""}],"badges":[],"createdAt":"2025-03-22 00:05:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6280645/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6280645/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80728675,"identity":"d4333a64-0762-4621-9b1b-cac9541ba1d9","added_by":"auto","created_at":"2025-04-16 12:11:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":145539,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Curve for Progression Free Survival.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure195XCIX.png","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/ec228f5628658392966c3197.png"},{"id":80727604,"identity":"31a88a24-3a72-4c6c-990f-b98cfd64db2f","added_by":"auto","created_at":"2025-04-16 12:03:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1698550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTherapy Outcomes Showing duration of Penultimate chemotherapy, TFI\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e, and PARPi Duration Followed by Doublet Maintenance\u003c/strong\u003e. TFI\u003csub\u003eP\u003c/sub\u003e, treatment-free interval from platinum-based chemotherapy; PARPi, PARP inhibitor.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure2new.png","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/fa6a7c6954658d118757ac72.png"},{"id":80728677,"identity":"7c8239e6-15d8-49f9-b12a-7d336b7afebe","added_by":"auto","created_at":"2025-04-16 12:11:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1413417,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstimated 6-Month Progression-Free Rate According to Prognostic Factors.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure320250215.png","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/e913abcdb00026d8a404bff8.png"},{"id":86529446,"identity":"c0ed24d5-e5db-4d2b-b27c-b551e691e2ac","added_by":"auto","created_at":"2025-07-11 16:38:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4104495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/ea7c2278-f0ec-4a89-9418-e747ba37f7ae.pdf"},{"id":80727602,"identity":"cbb924ba-0aa4-416e-9737-bd7e0b64b522","added_by":"auto","created_at":"2025-04-16 12:03:26","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":261593,"visible":true,"origin":"","legend":"Supplementary materials","description":"","filename":"SupplementarymaterialsHWCHO20250318.docx","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/fa6618511c2de880e4d3e752.docx"},{"id":80727605,"identity":"35effd77-3d38-4171-b9d4-ef7ccbda4a0f","added_by":"auto","created_at":"2025-04-16 12:03:26","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":496776,"visible":true,"origin":"","legend":"NIRVANA-R protocol","description":"","filename":"NIRVANARprotocolVer1.44clean20230207.docx.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6280645/v1/3f640fef20bc185f02367a2e.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Maintenance of PARP Inhibitor Rechallenge Plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP Inhibitor (KGOG 3056/NIRVANA-R)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMaintenance therapy with PARP inhibitors (PARPi) is the standard of care in patients with newly diagnosed advanced and platinum-sensitive, recurrent ovarian cancer, particularly in PARPi-na\u0026iuml;ve patients.\u003csup\u003e1, 2, 3, 4, 5, 6\u003c/sup\u003e This approach has significantly improved progression-free survival (PFS), and in the case of olaparib, has also demonstrated an overall survival (OS) benefit, leading to its integration into treatment paradigms worldwide \u003csup\u003e7, 8\u003c/sup\u003e. However, despite the clear benefit of PARPi in ovarian cancer, most patients eventually develop treatment resistance.\u003csup\u003e2, 3, 4, 5, 6, 9, 10\u003c/sup\u003e After progression on PARPi maintenance, the response to subsequent chemotherapy is reduced in ovarian cancer patients compared to those who were not previously administered PARPi.\u003csup\u003e10, 11, 12\u003c/sup\u003e Therefore, choosing subsequent therapy for patients who relapse after maintenance with a PARPi is challenging.\u003csup\u003e10, 13, 14\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eRecent studies have explored the concept of PARPi rechallenge in this context.\u003csup\u003e13, 15, 16\u003c/sup\u003e Although rechallenging with a PARPi after a response to platinum-based chemotherapy has demonstrated a modest benefit for PFS,\u003csup\u003e15, 16\u003c/sup\u003e the extent of this benefit and which patients might benefit most from this strategy is still under investigation.\u003c/p\u003e\n\u003cp\u003eThe OReO/ENGOT Ov-38 trial specifically addressed this clinical question by evaluating the efficacy and safety of PARPi rechallenge in patients with ovarian cancer who had previously received PARPi maintenance.\u003csup\u003e13\u003c/sup\u003e The results of this study have provided critical insights into the potential role of PARPi rechallenge in this patient population highlighting the need for further research to optimize maintenance therapy strategies in recurrent ovarian cancer.\u003c/p\u003e\n\u003cp\u003ePARPi combined with anti-angiogenic agents have shown promising efficacy, particularly in the treatment of ovarian cancer.\u003csup\u003e17, 18, 19, 20, 21\u003c/sup\u003e The combination therapy works by using bevacizumab to induce hypoxia in the tumor microenvironment, which can lead to homologous recombination deficiency (HRD) in cancer cells.\u003csup\u003e22\u003c/sup\u003e This HRD makes cancer cells more vulnerable to PARPi, and since the cells are unable to repair DNA damage, the effectiveness of the treatment is enhanced.\u003c/p\u003e\n\u003cp\u003eThis study aimed to build on these findings by investigating the combination of PARPi rechallenge with bevacizumab as maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer who had previously been treated with a PARPi.\u003c/p\u003e\n\n"},{"header":"Results","content":"\u003cp\u003eA total of 44 women were enrolled between July 2021 and November 2023. In our cohort, 39 patients (89%) had high-grade serous ovarian cancer, and 36% harbored somatic and/or germline BRCA1/2 mutations (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, 29 patients (66%) had received more than three prior lines of chemotherapy, 17 patients (39%) were included after receiving a maintenance PARPi as part of first-line therapy, and 34% had previously received anti-angiogenics (bevacizumab).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics at Baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNiraparib\u0026thinsp;+\u0026thinsp;Bevacizumab (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (53\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status score, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (75%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-grade serous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (89%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRCA status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRCA mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRCA wild-type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of prior lines of chemotherapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2nd line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (34%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3rd line and beyond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (66%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatinum-free interval (TFIp) of penultimate chemotherapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧12 to \u0026lt;\u0026thinsp;24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (45%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse to the most recent chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR (Partial response)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (61%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR (Complete response)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious anti-angiogenic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (34%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (66%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression on/after previous PARPi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression during PARPi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (68%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression after PARPi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (32%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of previous PARPi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLine of previous PARPi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (31%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 and beyond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of previous PARPi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (98%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of previous PARPi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlaparib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (52%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNiraparib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (43%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRucaparib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e+\u003c/sup\u003e3 Endometrioid, 2 low grade serous. PARPi\u0026thinsp;=\u0026thinsp;PARP inhibitor. ECOG\u0026thinsp;=\u0026thinsp;Eastern Cooperative Oncology Group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median duration of follow-up was 11\u0026middot;8 months at the data collection cut-off (June 1, 2024). About 31 patients discontinued trial treatment, while 13 continued (eFigure 1 in the Supplement). The reasons for study discontinuation were disease progression (n\u0026thinsp;=\u0026thinsp;21), withdrawn consent (n\u0026thinsp;=\u0026thinsp;5), adverse events (n\u0026thinsp;=\u0026thinsp;3), and physicians' decision to discontinue study treatment (n\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e \u003cp\u003eThe estimated 6-month progression-free rate was 68% [95% confidence interval (CI) 55\u0026ndash;85%], with a median PFS of 11\u0026middot;5 months [95% CI 7.9-not reached (NR)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The estimated 12-month progression-free rate was 46% (95% CI 31\u0026ndash;68%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe treatment overview for each patient, including the treatment-free interval (TFI\u003csub\u003eP,\u003c/sub\u003e platinum) after penultimate platinum-based chemotherapy and duration of doublet maintenance therapy, is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The 6-month time point from the start of doublet maintenance is marked with a vertical dashed line (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). About 20 patients had a TFI\u003csub\u003eP\u003c/sub\u003e \u0026ge;24 months after penultimate chemotherapy, and 43 patients had received PARPi as maintenance. In the cohort, 12 of the 44 patients showed disease progression within 6 months. This suggests that patients with a longer TFI\u003csub\u003eP\u003c/sub\u003e benefit more from doublet maintenance therapy with niraparib and bevacizumab, indicating that TFI\u003csub\u003eP\u003c/sub\u003e is a critical prognostic factor for better outcomes in terms of PFS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eExploratory subgroup analysis suggested an enhanced 6-month progression-free rate with maintenance of niraparib plus bevacizumab in patients with a long TFI\u003csub\u003eP\u003c/sub\u003e after penultimate platinum-based chemotherapy (TFI\u003csub\u003eP\u003c/sub\u003e \u0026ge;24 months vs. TFI\u003csub\u003eP\u003c/sub\u003e \u0026lt;24 months; 82% vs. 56%), in patients who had a complete response (CR) to the most recent chemotherapy [CR vs. partial response (PR); 86% vs. 57%], and in patients with normal-range CA-125 levels after the most recent chemotherapy (CA-125 0\u0026ndash;35 vs. \u0026gt;35 U/mL; 72% vs. 25%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, eFigure 2 in the Supplement). No clear association was observed between the number of prior lines of chemotherapy (\u0026le;\u0026thinsp;2 vs. \u0026gt;3), BRCA status, duration of prior PARPi exposure, type of previous PARPi (olaparib, niraparib, and rucaparib), progression during/after PARPi, or prior use of bevacizumab and the efficacy of niraparib plus bevacizumab maintenance (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNo new safety signals were observed for niraparib and bevacizumab treatment. The treatment-related adverse events (TRAEs) reported during the study are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs were reported in 12 (27\u0026middot;3%) patients. TRAEs were usually managed by dose modification, with only a few patients requiring discontinuation of treatment due to TRAEs (4 patients, 9.1%). None of the TRAEs resulted in death. eTable 3 in the Supplement presents the most common all-grade adverse events, which were thrombocytopenia (29\u0026middot;6%), hypertension (20\u0026middot;5%), anemia (18\u0026middot;2%), and neutropenia (18\u0026middot;2%). Overall, 27\u0026middot;3% of patients experienced grade 3 adverse events, with the most common being anemia (13\u0026middot;6%) and neutropenia (13\u0026middot;6%). The most common grade\u0026thinsp;\u0026ge;\u0026thinsp;3 niraparib-related and bevacizumab-related TRAEs were thrombocytopenia (27\u0026middot;3%) and hypertension (13\u0026middot;6%). No cases of Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML) were observed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;44\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny TRAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (90\u0026middot;9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNiraparib related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (81\u0026middot;8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (65\u0026middot;9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade\u0026thinsp;≧\u0026thinsp;3 TRAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (27\u0026middot;3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNiraparib related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (27\u0026middot;3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (13\u0026middot;6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny TRAE leading to discontinuation of any study treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9\u0026middot;1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscontinuation of niraparib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6\u0026middot;8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscontinuation of bevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4\u0026middot;5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny TRAE leading to study treatment interruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (59\u0026middot;1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNiraparib interruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (45\u0026middot;5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNiraparib dose reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (22\u0026middot;7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab interruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (31\u0026middot;8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny TRAE leading to death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eTRAE\u0026thinsp;=\u0026thinsp;Treatment-Related Adverse Events\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKGOG3056/NIRVANA-R is the first trial to report data on PARPi rechallenge with bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer patients who were previously treated with a PARPi. This study evaluated the doublet maintenance of niraparib rechallenge plus bevacizumab and demonstrated promising results. The study showed a 6-month progression-free rate of 68% and a median PFS of 11·5 months in patients with platinum-sensitive recurrent ovarian cancer who experienced disease progression after PARPi therapy.\u003c/p\u003e \u003cp\u003eThe findings from the NIRVANA-R study, which reported a 6-month progression-free rate of 68% and a median PFS of 11·5 months for PARPi rechallenge with bevacizumab, can be compared to results from the OReO and MOLTO studies, both of which explored PARPi rechallenge strategies in recurrent ovarian cancer. All three studies included patients with platinum-sensitive recurrence who had prior PARPi exposure, making them comparable in terms of study population. The OReO trial demonstrated that platinum-sensitive patients with relapsed ovarian cancer, who were previously treated with a PARPi, had a median PFS of 4·3 months in the overall population and 4·5 months in the BRCA-mutated cohort when rechallenged with olaparib, compared to 2·8 and 2·2 months, respectively, in patients administered placebo.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e This suggests that PARPi rechallenge alone provides modest benefits, but not as robust as the combination approach seen in NIRVANA-R. On the other hand, the MOLTO study, which evaluated olaparib rechallenge in a similar population with BRCA mutations, reported a median duration of olaparib rechallenge of 4·4 months, indicating that the addition of bevacizumab in NIRVANA-R may enhance the efficacy of PARPi rechallenge.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Overall, these results indicate that PARPi rechallenge can offer disease control in selected patients, but combining it with bevacizumab may further improve patient outcomes.\u003c/p\u003e \u003cp\u003eNIRVANA-R provides meaningful insights into which patients may benefit from about PARPi rechallenge. The 6-month progression-free rate was notably higher in patients with a longer TFI\u003csub\u003eP\u003c/sub\u003e after penultimate platinum-based chemotherapy, those who achieved a CR to the most recent chemotherapy, and those with normal-range CA-125 levels at baseline. These findings suggest that patients with a longer TFI\u003csub\u003eP\u003c/sub\u003e after penultimate chemotherapy, a CR to the most recent chemotherapy, or normal CA-125 levels at baseline benefited more from the combination of niraparib and bevacizumab. These results align with findings from the OReO study, in which patients who had a CR at baseline and a longer platinum-free interval between penultimate and the most recent platinum-based chemotherapy experienced greater benefit from olaparib rechallenge.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e In both the OReO and NIRVANA-R trials, the median PFS significantly improved in these subgroups, highlighting the importance of baseline characteristics in predicting the efficacy of PARPi rechallenge.\u003c/p\u003e \u003cp\u003eDespite the significant findings in certain subgroups, this study found no clear association between the efficacy of niraparib plus bevacizumab maintenance therapy and factors such as the number of prior lines of chemotherapy (≤ 2 vs. \u0026gt;3), BRCA status, duration of prior PARPi exposure, type of previous PARPi (olaparib, niraparib, or rucaparib), progression during or after PARPi, and historical use of bevacizumab. The lack of significant differences in PFS based on the number of prior lines of chemotherapy is consistent with the findings from the OReO study, which also observed minimal variation in PFS across different prior treatment lines. Similarly, in both the present study and the OReO study, no significant differences in PFS were observed based on BRCA status.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e However, the absence of substantial differences in PFS based on whether progression occurred during or after PARPi treatment differs from the findings reported in the OReO study and the PAOLA-1 post-hoc analysis, which showed a more pronounced difference in outcomes based on the timing of progression relative to PARPi use.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Nonetheless, the NIRVANA-R study also indicated some variation in PFS between the two groups and reported a median PFS of 11·3 months in patients with disease progression during PARPi treatment and PFS of 14·9 months in patients with disease progression after PARPi treatment. While this difference was not significant, the numerically longer PFS in the progression-after-PARPi group suggests that patients who experience progression after completing PARPi may still respond to subsequent platinum therapy. In contrast, those who progress on PARPi may exhibit poorer responses to platinum but could still be considered for PARPi retreatment if they demonstrate sensitivity to subsequent platinum-based regimens.\u003c/p\u003e \u003cp\u003eWhile the NIRVANA-R study provides valuable insights into the efficacy of PARPi rechallenge combined with bevacizumab in recurrent ovarian cancer, it leaves several critical questions unanswered that need to be addressed in future research. One key limitation of this study is that the efficacy of PARPi rechallenge in patients who relapse after a certain period following the completion of PARPi therapy, particularly after a treatment-free interval, still needs to be investigated. Another important aspect requiring further investigation is understanding the reason for discontinuing the initial PARPi therapy, whether due to disease progression or other factors such as adverse events, and how this affects prognosis and response to subsequent PARPi rechallenge. Addressing these questions will be crucial in refining patient selection for PARPi rechallenge and optimizing treatment strategies for recurrent ovarian cancer.\u003c/p\u003e \u003cp\u003eThe NIRVANA-R study's safety profile demonstrated manageable adverse events that were similar to those reported in other studies involving PARPi rechallenge or PARPi-bevacizumab combinations (such as OREO, PAOLA-1, and OVARIO). In the NIRVANA-R study, the most common all-grade adverse events included thrombocytopenia (29·6%), hypertension, anemia, and neutropenia, and 27·3% of patients reported grade ≥ 3 events. These findings are comparable to that of the OVARIO study where the most common any-grade adverse events related to niraparib and/or bevacizumab were thrombocytopenia, fatigue, and anemia.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e However, the NIRVANA-R study reported a slightly lower incidence of severe (grade ≥ 3) events compared to the PAOLA-1 study (57%) and OVARIO study (39%).\u003csup\u003e17, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The OREO study which focused on olaparib rechallenge also observed similar incidence of hematological toxicities such as anemia and neutropenia, but reported a lower incidence of hypertension and thrombocytopenia compared to NIRVANA-R.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Despite these differences, the rates of dose modifications and treatment discontinuations due to adverse events were comparable between NIRVANA-R and OREO. A comparison of these findings suggested that a combination of niraparib and bevacizumab in NIRVANA-R is consistent with known safety profiles from similar studies, indicating that the addition of bevacizumab did not substantially increase the toxicity of PARPi rechallenge. Importantly, no new safety signals were identified in NIRVANA-R and no cases of treatment-related deaths were reported, highlighting the manageable safety profile of the niraparib and bevacizumab combination in this setting.\u003c/p\u003e \u003cp\u003eThis study has several strengths including a robust exploration of the efficacy of PARPi rechallenge combined with bevacizumab in recurrent ovarian cancer. The study design allowed for meaningful subgroup analyses, providing insights into the profile of patients which may benefit the most from this treatment approach, especially patients with a longer TFI\u003csub\u003eP\u003c/sub\u003e after penultimate platinum-based chemotherapy and favorable responses to most recent platinum-based chemotherapy. However, the study has some limitations. The sample size is relatively small. This may limit the generalizability of the findings. Additionally, the subgroup analysis was exploratory in nature and was not sufficiently statistically powered for definitive conclusions. This emphasizes the need for cautious interpretation of these results.\u003c/p\u003e \u003cp\u003eThe present study did not meet its primary endpoint, but this may be due to an overly optimistic statistical assumption rather than a lack of treatment efficacy. At the time of the study, there was limited clinical evidence indicating that patients who relapse after PARPi maintenance therapy often exhibit reduced responses to subsequent chemotherapy. The anticipated 6-month progression-free rate of 50% without doublet maintenance may have been an overestimate for this population. In the OREO study, for example, the placebo group had a PFS of only 2·8 months, with a 6-month progression-free rate of approximately 10%.\u003csup\u003e10\u003c/sup\u003e Similar finding have been reported in other studies involving PARPi.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn conclusion, although the NIRVANA-R study did not meet its predefined primary endpoint, the study provides important insights into the potential role of PARPi rechallenge with bevacizumab as a maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer who were previously been treated with a PARPi. The study demonstrated a 6-month progression-free rate of 68% and a median PFS of 11.5 months in overall population, with more pronounced benefits observed in subgroups such as, those with a longer TFI\u003csub\u003eP\u003c/sub\u003e after penultimate platinum-based chemotherapy, CR or normal CA-125 level in response to the most recent chemotherapy. However, the study raises important questions about the impact of historical PARPi exposure and the timing of progression on the efficacy of rechallenge, underscoring the need for further research to refine patient selection and optimize treatment strategies. Overall, while the combination of niraparib and bevacizumab is promising, more definitive studies are needed to fully understand its role in managing recurrent ovarian cancer after PARPi therapy.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy Design and Participants\u003c/h2\u003e\u003cp\u003eThe KGOG 3056/NIRVANA-R trial is a multi-center, investigator-initiated, single-arm phase II trial designed to evaluate the combination of niraparib and bevacizumab as maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer who were previously treated with a PARPi. Eligible patients were offered niraparib and bevacizumab as maintenance treatment, continued until unacceptable toxicity developed or the patient no longer derived clinical benefit due to disease progression.\u003c/p\u003e\u003cp\u003eThe major inclusion criteria for the trial were as follows: prior treatment with a PARPi; ≥2 previous courses of platinum-based chemotherapy; complete or partial response to the most recent platinum-based chemotherapy; TFI\u003csub\u003eP\u003c/sub\u003e from penultimate platinum-based chemotherapy of ≥ 12 months; serous, clear cell, or low-grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; age ≥ 20 years; and ECOG performance status of 0–1.\u003c/p\u003e\u003cp\u003e The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Approval was obtained from national and local research ethics committees, and all patients provided written informed consent.\u003c/p\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003ePatients were enrolled within 8 weeks of receiving their last dose of platinum-based chemotherapy. Oral niraparib (individual starting dose of 200 or 300 mg) was administered once daily, and bevacizumab (15 mg/kg) was administered every 3 weeks as an intravenous infusion.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Treatment continued until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first.\u003c/p\u003e \u003cp\u003eTumors were assessed every 12 weeks according to RECIST v1\u0026middot;1 until radiologic progression. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4\u0026middot;03). Adverse events were graded according to version 5\u0026middot;0 of the same criteria. Criteria for treatment interruptions and dose reductions are provided in the Supplementary Information.\u003c/p\u003e \u003cp\u003eProvision of archival tissue (initial diagnostic tissue before PARPi treatment) was mandatory, while baseline biopsy (after PARPi) and blood samples were optional.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary objective was to determine the efficacy of niraparib plus bevacizumab maintenance therapy in patients previously treated with a PARPi, as assessed by the 6-month progression-free rate. Progression was defined according to RECIST (version 1\u0026middot;1), including progression without objective evidence, such as global deterioration in health status attributable to disease and requiring a change in therapy.\u003c/p\u003e \u003cp\u003eThe secondary objectives were to evaluate the 12-month progression-free rate, PFS, OS, time until the first subsequent treatment (from randomization until first subsequent surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, other treatment, or death), safety, and predictive biomarkers correlated with response to niraparib plus bevacizumab. PFS was defined as the time from the start of treatment until disease progression or death from any cause. OS was defined as the time from the first treatment until death from any cause.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eClinical characteristics were summarized as frequency (percentage) for categorical variables and as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for continuous variables. Sample size computation was based on a Simon optimal two-stage design. Assuming a 5% significance level and 80% statistical power, we hypothesized a 50% 6-month progression-free rate under the null hypothesis and at least 70% under the alternative hypothesis for patients with platinum-sensitive recurrent ovarian cancer. In the first stage, 22 patients were enrolled. If 9 or fewer progressions were observed at 6 months, an additional 22 patients were enrolled later. Hence, a total of 44 patients were enrolled. \u003c/p\u003e \u003cp\u003eThe safety evaluable set included all patients who began treatment. The 6-month and 12-month progression-free rates were estimated using the Kaplan-Meier method and were compared between groups using the log-rank test. All reported \u003cem\u003eP\u003c/em\u003e-values were two-sided, a \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;05 was considered significant. All data analyses were performed using R software (version 4\u0026middot;4\u0026middot;1; R Foundation for Statistical Computing, Vienna, Austria). Data collection cut-off date was set as June 1, 2024.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJYL contributed to the design of the study. JYP, MCL, BGK, MCC, JWK, DHJ, JYL and HWC Korea Gynecologic Oncologic Group (KGOG) members recruited patients and collected the data. HWC, SBH and JYL contributed to data analysis and interpretation. HWC, EP and JYL drafted the manuscript. HWC and JYL verified all study data. The final version was approved to be submitted by all authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJung-Yun Lee\u003c/p\u003e\n\u003cp\u003eConsulting or Advisory Role: AstraZeneca, MSD, Roche, Takeda\u003c/p\u003e\n\u003cp\u003eResearch Funding: Clovis Oncology, Immunogen, Janssen Oncology, Merck, MSD, Synthon, Eisai, Mersan, Ascendis Pharma, AstraZeneca, Novartis, OncoQuest Pharmaceutical, Roche, Seagen, Takeda \u003c/p\u003e\n\u003cp\u003eNo other potential conflicts of interest were reported.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Cancer Center of the Republic of Korea\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDe-identified participant data will be accessible to qualified researchers upon request, commencing 24 months after the study\u0026rsquo;s completion, including follow-up. Interested researchers should submit a methodologically sound research proposal to the corresponding author and sign a data access agreement to obtain access. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by a grant under the National Cancer Center of the Republic of Korea (No. : RS-2024-00360954)\u003c/p\u003e\n\n\n"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLedermann J\u003cem\u003e, et al.\u003c/em\u003e Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e366\u003c/strong\u003e, 1382-1392 (2012).\u003c/li\u003e\n \u003cli\u003eMirza MR\u003cem\u003e, et al.\u003c/em\u003e Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e375\u003c/strong\u003e, 2154-2164 (2016).\u003c/li\u003e\n \u003cli\u003ePujade-Lauraine E\u003cem\u003e, et al.\u003c/em\u003e Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. \u003cem\u003eLancet Oncol\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 1274-1284 (2017).\u003c/li\u003e\n \u003cli\u003eGonzález-Martín A\u003cem\u003e, et al.\u003c/em\u003e Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e381\u003c/strong\u003e, 2391-2402 (2019).\u003c/li\u003e\n \u003cli\u003eMonk BJ\u003cem\u003e, et al.\u003c/em\u003e A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e40\u003c/strong\u003e, 3952-3964 (2022).\u003c/li\u003e\n \u003cli\u003eMoore K\u003cem\u003e, et al.\u003c/em\u003e Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e379\u003c/strong\u003e, 2495-2505 (2018).\u003c/li\u003e\n \u003cli\u003eGonzález-Martín A\u003cem\u003e, et al.\u003c/em\u003e Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. \u003cem\u003eAnn Oncol\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 833-848 (2023).\u003c/li\u003e\n \u003cli\u003eTew WP, Lacchetti C, Kohn EC, PARP Inhibitors in the Management of Ovarian Cancer Guideline Expert Panel. 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Understanding and overcoming resistance to PARP inhibitors in cancer therapy. \u003cem\u003eNat Rev Clin Oncol\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 773-791 (2021).\u003c/li\u003e\n \u003cli\u003eFrenel JS\u003cem\u003e, et al.\u003c/em\u003e Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial. \u003cem\u003eAnn Oncol\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 1021-1028 (2022).\u003c/li\u003e\n \u003cli\u003ePark J\u003cem\u003e, et al.\u003c/em\u003e Second-line olaparib maintenance therapy is associated with poor response to subsequent chemotherapy in BRCA1/2-mutated epithelial ovarian cancer: A multicentre retrospective study. \u003cem\u003eGynecol Oncol\u003c/em\u003e \u003cstrong\u003e165\u003c/strong\u003e, 97-104 (2022).\u003c/li\u003e\n \u003cli\u003eHarter P\u003cem\u003e, et al.\u003c/em\u003e Efficacy of subsequent therapies in patients (pts) with advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of olaparib (ola) maintenance. \u003cem\u003eJ Clin Oncol \u003c/em\u003e\u003cstrong\u003e41\u003c/strong\u003e, 5550 (2023).\u003c/li\u003e\n \u003cli\u003ePujade-Lauraine E\u003cem\u003e, et al.\u003c/em\u003e Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial. \u003cem\u003eAnn Oncol\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 1152-1164 (2023).\u003c/li\u003e\n \u003cli\u003eKim YN\u003cem\u003e, et al.\u003c/em\u003e Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With BRCA-Mutated Ovarian Cancer. \u003cem\u003eClin Cancer Res\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 2725-2734 (2023).\u003c/li\u003e\n \u003cli\u003eLheureux S\u003cem\u003e, et al.\u003c/em\u003e EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression. \u003cem\u003eClin Cancer Res\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 4206-4215 (2020).\u003c/li\u003e\n \u003cli\u003eMorgan RD\u003cem\u003e, et al.\u003c/em\u003e Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial. \u003cem\u003eClin Cancer Res\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 2602-2611 (2023).\u003c/li\u003e\n \u003cli\u003eRay-Coquard I\u003cem\u003e, et al.\u003c/em\u003e Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e381\u003c/strong\u003e, 2416-2428 (2019).\u003c/li\u003e\n \u003cli\u003eLiu JF\u003cem\u003e, et al.\u003c/em\u003e Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. \u003cem\u003eLancet Oncol\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 1207-1214 (2014).\u003c/li\u003e\n \u003cli\u003eMirza MR\u003cem\u003e, et al.\u003c/em\u003e A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV24. \u003cem\u003eCancer Chemother Pharmacol\u003c/em\u003e \u003cstrong\u003e84\u003c/strong\u003e, 791-798 (2019).\u003c/li\u003e\n \u003cli\u003eKim YN\u003cem\u003e, et al.\u003c/em\u003e Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045. \u003cem\u003eInt J Cancer\u003c/em\u003e \u003cstrong\u003e153\u003c/strong\u003e, 2032-2044 (2023).\u003c/li\u003e\n \u003cli\u003eKim YN\u003cem\u003e, et al.\u003c/em\u003e Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4. \u003cem\u003eNat Commun\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 5476 (2023).\u003c/li\u003e\n \u003cli\u003eAlvarez Secord A, O'Malley DM, Sood AK, Westin SN, Liu JF. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. \u003cem\u003eGynecol Oncol\u003c/em\u003e \u003cstrong\u003e162\u003c/strong\u003e, 482-495 (2021).\u003c/li\u003e\n \u003cli\u003eHardesty MM\u003cem\u003e, et al.\u003c/em\u003e OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. \u003cem\u003eGynecol Oncol\u003c/em\u003e \u003cstrong\u003e166\u003c/strong\u003e, 219-229 (2022).\u003c/li\u003e\n \u003cli\u003eLi N\u003cem\u003e, et al.\u003c/em\u003e Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial. \u003cem\u003eJAMA Oncol\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 1230-1237 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6280645/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6280645/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical benefit in prolonging progression-free survival (PFS) in ovarian cancer. However, the efficacy of subsequent chemotherapy after PARPi progression is limited. While modest benefits have been seen with PARPi rechallenge, the efficacy of rechallenging with PARPi in combination with bevacizumab remains unknown. NIRVANA-R, a phase 2 study, evaluated niraparib rechallenge with bevacizumab in 44 patients with platinum-sensitive recurrent ovarian cancer previously treated with PARPi. The estimated 6-month PFS rate, the primary endpoint, was 68% [95% confidence interval (CI): 55–85%]. Notably, higher 6-month PFS rates were observed in patients with a longer treatment-free interval after the penultimate chemotherapy and in those who achieved a complete response to the most recent chemotherapy. Median PFS was 11.5 months [95% CI: 7.9–not reached]. This is the first report of niraparib rechallenge with bevacizumab as maintenance therapy in this patient population. The combination showed promising efficacy, especially in patients who responded well to prior platinum-based chemotherapy.","manuscriptTitle":"Maintenance of PARP Inhibitor Rechallenge Plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP Inhibitor (KGOG 3056/NIRVANA-R)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-16 12:03:22","doi":"10.21203/rs.3.rs-6280645/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4a4540cf-e8ad-46b6-81c9-8a94fd221e57","owner":[],"postedDate":"April 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47046370,"name":"Health sciences/Oncology/Cancer/Gynaecological cancer/Ovarian cancer"},{"id":47046371,"name":"Health sciences/Oncology/Cancer/Gynaecological cancer"}],"tags":[],"updatedAt":"2025-07-11T16:30:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-16 12:03:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6280645","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6280645","identity":"rs-6280645","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}